DESCRIPTION: The long-term goal of this proposal is to advance the clinical application of hand and composite tissue transplantation by reducing the adverse effects of immunosuppressive therapy. The role of composite tissue transplantation is based on functional and aesthetic reconstruction following trauma, congenital defect or cancer resection. The application of allogeneic reconstruction could avoid the limitations of donor-site morbidity and availability, and offer greater potential for the reconstruction of specialized structures such as limb and craniofacial components. A reliable murine model has been developed to study the immunology of composite tissue transplantation and to utilize recently available antibody therapies and genetically manipulated animals. Blockade of the CD40 costimulatory pathway is an important component of strategies that have been successful in prolonging the survival of skin and organ allografts in rodent and large animal models. This strategy has not been studied in a model of limb transplantation. The mechanism of action for the induction of immune unresponsiveness and the resistance to tolerance when used as a single agent in organ transplantation continues to be investigated. CD40 blockade appears to be most successful when combined with other therapies including donor bone marrow transfusion. The bone marrow component of a limb allograft distinguishes it from organ allografts, and may therefore have a greater potential for the induction of tolerance. The specific aims of this proposal are: 1) To determine the mechanism of resistance to limb allograft tolerance after treatment with CD40 blockade. 2) To develop a combined regimen for the induction of tolerance to limb allografts based on CD40 costimulation blockade. 3) To determine the mechanism of donor-specific immune unresponsiveness by a combined regimen based on CD40 blockade. Assessment techniques include mixed lymphocyte culture, flow cytometry, and the ELISPOT assay, in conjunction with histological and immunohistochemical assessment of allograft viability and rejection. The broad objective of this proposal is to improve the quality of reconstructive options and the quality of life for patients with devastating deformities.